We will continue to synthesize constrained cyclic analogs of somatostatin and enkephalin, incorporating peptidomimetics and the pairwise retro-inverso modifications to help develop structure-biological activity relationships for these important biological systems. The selection of target analogs for synthesis is achieved with the aid of molecular mechanics. The molecular design of target analogs include the biological and conformational results based upon our past synthetic efforts. Conformational studies are carried out using nuclear magnetic resonance spectroscopy and molecular dynamics. Thus our general approach involves synthesis, biological screenings, spectroscopy, and computer simulations. In the area of somatostatin we are synthesizing target molecules based on the structure of the superactive hexapeptide, c(Pro-Phe- D-Trp-Lys-Thr-Phe). With these compounds we are able to examine hypotheses of structural requirements for biological activity. Incorporation of peptidomimetics and retro-inverso modifications allow us to probe the importance to biological activity of the bridging linkage, specific intramolecular hydrogen bonds as well as the main chain and side chain conformations. In the area of enkephalins we continue to explore target analogs based on the structure of the highly active opiate Tyr-c(D-A2bu- Gly-Phe-Leu). From our previous investigations of modified analogs we have preposed a hypothesis for the selectivity at the mu and delta opiate receptors. Future target analogs will allow us to test this hypothesis. We have also begun the synthesis of a new series of analogs incorporating constrained peptidomimetics to compare structural features of the peptide-like opiates with alkaloids. The constrained somatostatin and enkephalin analogs provide us with insight into structure-biological activity relationships. From these findings we hope to develop new drug candidates as hormones and opiates.